Glutamic acid functions also as an excitatory neurotransmitter in the body, and is associated with mental disorder and motor dysfunction based on neurodegeneration as observed in brain and spinal cord injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and so on. Glutamate receptors are classified into N-methyl-D-aspartate (hereinbelow, referred to as “NMDA”) receptors; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (hereinbelow, referred to as “AMPA”) receptors and kainate receptors, both of which are non-NMDA receptors; and metabotropic receptors. Glutamate receptors allow the influx of sodium ions and potassium ions into the cells upon activation by glutamic acid or aspartic acid. Particularly, NMDA receptors are known to allow also the influx of calcium ions upon activation. Therefore, while NMDA receptors are associated with the formation of memory and learning, neural development, and so on in the mammalian brain, hyperexcitation of NMDA receptors causes irreversible necrosis of nerve cells in the brain due to the massive influx of calcium into the cells, resulting in damage such as movement disorder, perceptual disorder, and abnormal behavior as a sequel (Non Patent Literatures 1 to 3).
As described above, NMDA receptors are associated with various nervous system diseases, and NMDA receptor inhibitors are expected to serve as therapeutic drugs for these diseases. As NMDA receptor inhibitors, memantine, macrocyclic compounds, and polyamine compounds are reported (Patent Literatures 1 to 3).
Meanwhile, acid-sensing ion channel 1a (ASIC1a) is one of the ion channels, and activation of ASIC1a causes an influx of sodium into the cells, followed by depolarization. Depolarization of the cell membrane promotes activation of NMDA receptors, and the activated NMDA receptors allow the influx of sodium and calcium therethrough. Calcium which has flowed in through NMDA receptors activates the enzyme CaMK II, and the activated CaMK II then mediates phosphorylation of ASIC1. By the phosphorylated ASIC1, the channel activity is promoted (Non Patent Literatures 4 and 5).
As described above, since ASIC1a is one of the channels for sodium and the like, it is associated with diuretic action, neurodegenerative disease, and so on. Amiloride, which is an ASIC1a inhibitor, is not only used as a diuretic drug but also expected to be effective for neurodegenerative disease (Non Patent Literature 6).